Abstract In mammals, fetal cardiac myocytes (CMs) proliferate robustly, contributing to the growth of the heart in utero. Postnatally, cell cycle genes are dramatically down-regulated and the ability of CMs to enter the cell cycle is lost after postnatal day 7. The lack of cell cycle gene expression in adult CMs (ACMs) suggests these genes are stably silenced and no longer able to respond to growth stimuli. As a result of this very limited proliferative potential, the mammalian heart has long been thought of as a non-regenerative organ. This has been challenged by increasing evidence demonstrating that postnatal CMs do proliferate and contribute to myocardial renewal but at a very low rate. The lack of cell cycle gene expression in ACMs is reminiscent of other biologic processes such as senescence or cell cycle checkpoints where epigenetic mechanisms stably silence gene transcription through the formation of heterochromatin. This proposal hypothesizes that cell cycle genes are stably silenced in ACMs through a highly regulated process that involves trimethylation of histone H3 on lysine 9 (H3K9me3), which then recruits the epigenetic machinery at cell cycle promoters leading to stable gene silencing. The corollary of this model, if true, is that manipulating this epigenetic process and the proteins that mediate heterochromatin formation could promote cell cycle re-entry in ACMs, a first step towards cardiac proliferation and myocardial regeneration. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page